Parkinson's disease (PD) is a chronic neurodegenerative disorder that affects millions of persons worldwide.. The etiology of PD remains largely unexplained. There is, however, increasing experimental and epidemiologic evidence that environmental toxicants, including those commonly found at hazardous waste sites, are etiologically related to the development of PD. Recent thinking on PD causation also emphasizes the significance of gene/environment interactions, whereby persons who carry genotypes predictive of either a diminished capacity for chemical detoxification or enhanced propensity to activate pro-neurotoxicants are most susceptible to environmentally-induced PD. We are proposing to extend our ongoing population-based case-control study which is investigating the effects of environmentally and genotypic risk factors, and their interactions, on risk of PD. The target goal of the study will be 400 newly diagnosed idiopathic PD cases and 6500 age. gender/race- matched controls free of PD and other major neurodegenerative disorders. Study subjects are identified from a defined population source, Group Health Cooperative of Puget Sound, Washington. Exposures of greatest a priori interest are industrial solvents, heavy metals, and pesticides. We will also investigate the unique and interactive associations of known polymorphisms of genes encoding enzymes pertinent to environmental chemical activation and/or detoxification, including: type B monoamine oxidase (MAO-BN), cytochromes P450 (CYP) 2D6 and 2E1, and the M1, T1, and P1 isozymes of glutathione S-transferase (GST). A unifying hypothesis of PD pathogenesis underlying this research is that chemical that provoke oxidative stress reactions destroy dopaminergic neurons preferentially among persons with unknown genetic polymorphisms of MAO-B and GSTM. In addition, we will conduct a series of in vitro experiments to determine the functional significance of several MAO-B and GST polymorphisms to characterize further mechanistic relations with PD pathogenesis. Direct interactions are planned between this study and projects 3 (Dr. Costa) and 4 (Dr. Keiffer) that also address environmentally-related neurotoxicity. Insofar the causation of PD remains elusive, this investigation will generate important new scientific and public health knowledge. Furthermore, this project may ultimately serve as model approach for investigating the complex interplay between low-level environmental exposures, as would be anticipated to result from hazardous waste sites, and host factors on risk for neurodegenerative disorders.